Many substituted-benzo[b]thiophene derivatives have hitherto been synthesized and a plurality of the substituted-benzo[b]thiophene derivatives have been used as raw materials for chemicals, medicines and the like. Among them, 3-substituted-benzo[b]thiophene derivatives represented by the following formula (XIII): wherein, R17 to R20 represent simultaneously or each independently a hydrogen atom, a halogen atom, a trihalomethyl group, a C1-4 alkyl group, a C1-4 alkoxy group or a cyano group; and X represents a hydroxy group or a halogen atom, are exceedingly important as intermediates in preparing pharmacologically active compounds. For example, among the 3-substituted-benzo[b]thiophene derivatives represented by formula (XIII), compounds in which R17 to R20 represent each a hydrogen atom; and X represents a bromine atom, compounds in which R17 represents a methyl group; R18 to R20 represent each a hydrogen atom; and X represents a bromine atom, compounds in which R18 represents a methyl group; R17, R19 and R20 represent each a hydrogen atom; and X represents a bromine atom and compounds in which R17 and R19 represent each a methyl group; R18 and R20 represent each a hydrogen atom; and X represents a bromine atom are capable of providing raw materials and the like for synthetic intermediates for benzimidazole derivatives as set forth in WO01/53291 and may be regarded as extremely important as intermediates in preparing pharmacologically active compounds. The benzimidazole derivatives as set forth in WO01/53291 are pharmaceutically useful benzimidazole derivatives and are considered to be promising as compounds applicable to prophylactic and/or therapeutic agents for various diseases including respiratory diseases such as bronchial asthma, sclerosing vascular lesions, intravascular stenosis and peripheral circulatory disorders.
Especially, because of structural features of 3,4-disubstituted-benzo[b]thiophene derivatives represented by the following formula (I): wherein, R1 represents a halogen atom, a trihalomethyl group, a C1-4 alkyl group or a C1-4 alkoxy group; and X represents a hydroxy group or a halogen atom, isomers in the 4- and 6-positions thereof are produced when the benzo[b]thiophene skeleton is synthesized. Since the separation of the isomers is extremely difficult, no report has been made of the synthesis of the 3,4-disubstituted-benzo[b]thiophene derivatives. However, the 3,4-disubstituted-benzo[b]thiophene derivatives are remarkably expected as raw materials for highly active substances in development of medicines due to characteristic structures thereof.
Techniques described in “J. Chem. Soc., Chem. Comm., 848 (1974)” are cited as techniques related to synthesis of compounds of the present invention. The report has been made on reactions for introducing a propargyl group into benzenethiol, then carrying out oxidizing reaction, providing compounds represented by the following formula (XIV): wherein, all of R21 and R22 are hydrogen atoms or a benzene ring may be formed of R21 and R22, then subjecting the resulting compounds represented by the formula (XIV) to thermal rearrangement reaction, affording compounds represented by the following formula (XV): wherein, all of R21 and R22 are hydrogen atoms or a benzene ring may be formed of R21 and R22, further subjecting the resulting compounds represented by the formula (XV) to thermal rearrangement reaction in the presence of p-toluenesulfonic acid in water-dioxane and providing compounds represented by the following formula (XVI): wherein, all of R21 and R22 are hydrogen atoms or a benzene ring may be formed of R21 and R22.
The reference, however, describes no 4-substituted-3-hydroxymethyl-benzo[b]thiophene derivative. As to the process for preparation, only conditions: in the presence of p-toluenesulfonic acid-dioxane are described.
When synthesis is carried out under the conditions described in the reference, by-products other than the 6-substituted-3-hydroxymethyl-benzo[b]thiophene derivatives which are isomers are produced in a higher proportion than that of the processes for preparation of the present invention. Thereby, the purification with column chromatography becomes essential and the synthesis under the conditions described in the reference is not suitable as an industrial process for preparation at all. In addition, a fraction of the objective substance obtained by column chromatography is a mixture of a 4-substituted-3-hydroxymethyl-benzo[b]thiophene and a 6-substituted-3-hydroxymethyl-benzo[b]thiophene in a ratio of about 3:2. The reference describes no method for separating the 4-substituted-3-hydroxymethyl-benzo[b]thiophene from the mixture. Complete separation cannot be carried out even by column chromatographic purification. The synthesis of the 4-substituted-3-hydroxymethyl-benzo[b]thiophene was very difficult according to the synthetic methods which have been reported up to present.
The yield of the 3-hydroxymethylbenzo[b]thiophene in the synthesis thereof in the reference is as low as 64% due to the synthesis of by-products, and the synthesis is industrially disadvantageous because steps are increased by taking the subsequent halogenation (synthesis of a 3-halomethyl-benzo[b]thiophene) and the like into consideration.
As other synthetic methods for the 3-halomethyl-benzo[b]thiophene derivatives, there are methods for reacting p-toluenethiol with bromoacetaldehyde diethyl acetal, providing a sulfide, then cyclizing the resulting sulfide with polyphosphoric acid, affording 5-methyl-benzo[b]thiophene, subsequently reacting the resulting 5-methyl-benzo[b]thiophene with hydrogen chloride gas-formaldehyde and introducing chloromethyl group [J. Chem. Soc., C, 514 (1968)] or methods for carrying out the Friedel-Crafts reaction of benzo[b]thiophene, synthesizing a 3-chloroacetyl-benzo[b]thiophene derivative to be a raw material [J. Chem. Soc., Perkin Trans. 2, 1250, (1973)], hydrolyzing the resulting 3-chloroacetyl-benzo[b]thiophene derivative and then reducing and halogenating the hydrolysis product and the like. In any of the methods, halomethyl groups are introduced into both the 2- and the 3-positions, and the selectivity thereof is not always high. Besides, the separation of the 3-halomethyl-benzothiophene derivatives from the 2-halomethyl-benzothiophene derivatives is extremely difficult.
From the above situation, the 4-substituted-3-hydroxymethyl-benzo[b]thiophene derivatives represented by formula (I) have been demanded and an efficient and simple synthetic method for the 4-substituted-3-hydroxymethyl-benzo[b]thiophene derivatives has been desired.
Furthermore, an efficient and simple synthetic method for the 3-halomethyl-benzo[b]thiophene derivatives has been desired.